–CV disease is the top killer but pharma is pulling back on developing new drugs.
Although cardiovascular disease is the number one cause of death in the world fewer cardiovascular drugs are under development now than in the past, according to a study published in JACC: Basic to Translational Science.
Thomas Hwang and colleagues at Brigham and Women’s Hospital tracked the development of drugs from 1990 through 2012. During the trial period, 347 cardiovascular drugs entered Phase 1 testing, with the most common types being antihypertensive agents, lipid-lowering agents and anticoagulants. The number of cardiovascular drugs entering clinical trials in all stages of development declined over time. During the same time the opposite trend was observed for cancer drugs.
“These findings are not entirely glass-half empty,” said Douglas Mann, editor-in-chief of JACC: Basic to Translational Science. “Part of the decline in new drugs is that there are less ‘me too’ drugs that are similar to those already available. The study also refutes the premise that cardiovascular drugs are often riskier to develop than drugs in other clinical categories.”
Despite what it might seem to some observers, the study did not find that cardiovascular drugs are more likely to fail in phase 3 trials than other drugs. It is also interesting to note that although most cardiovascular drugs have been sponsored by large drug companies, over time there has been an increase in drugs coming from small and medium-sized companies.
In an accompanying editorial, FDA officials, including senior author FDA commissioner Robert Califf, write that they are encouraged by the fact that half of the drugs entering phase 3 targeted a novel biological pathway. This “indicates a priority for truly novel targets in drug development.”
The FDA authors also point to “a viewpoint that given the large number of beneficial therapies in CV disease, the stringent requirements for demonstration of benefit in clinical outcomes, although justified, may be pushing drug developers to areas in which smaller trials with less stringent clinical outcome measurements are required.” This may explain the opposite trend for cancer drugs, since “development programs in oncology are generally smaller and less expensive, and the value placed on targeted therapies has allowed sponsors to recoup the costs by charging a lot to a few, although this pricing approach is increasingly under scrutiny.”
I asked several of my regular sources for comments on this topic. Their thoughts ranged widely:
Sanjay Kaul: Not only does drug development follow science, but also the return on investment. It has become increasingly difficult to show incremental treatment benefits in the cardiovascular space relative to other disciplines such as oncology and neuroscience. All the low hanging fruit has been plucked! So, not surprising to see the changing landscape of Big Pharma. The FDA editorial proposes non-traditional sources of evidence such as the electronic health record to render evidence generation more efficient in the cardiovascular space. However, in my opinion the quality of the evidence generated might come at the price of increasing, not diminishing, regulatory uncertainty. Reconciling ‘efficiency’ with ‘stringency’ is going to be the main challenge as we embark on the course proposed by the FDA.
Milton Packer: “The development of cardiovascular drugs is definitely on the decline. This is not related to a lack of need or a lack of innovation. It may be related to the very sluggish response that practitioners have to the introduction of new cardiovascular drugs. In the modern era, using a new drug means documenting a need for it (generally by completing a form). Oncologists complete the process with enthusiasm; cardiologists do not. It is not a matter of cost; it is related to physician attitude and behavior. Devices are not being ignored because there is a direct physician benefit; this is simply not true of drugs. As a result, drug discoveries that should be translated into the clinic are not being used, and often, that means that the results of clinical trials or guidelines are not followed. Under such circumstances, why should industry develop new cardiovascular agents? The reluctance that cardiologists display for new drugs creates a self-fulfilling prophecy. If we do not utilize new drugs appropriately, we will not have any.”
Steve Nissen:“We’ve had for several decades a tremendous run with a series of extraordinary therapies like ACE inhibitors and statins and they have markedly reduced morbidity and mortality from cardiovascular disease. We’re now in an era where new drugs must show benefit when given on a background of the evidence based therapies that are appropriate and for ethical reasons must be given to patients. It’s hard to show an incremental benefit on top of therapies that have high value and very low cost. So the value equation in developing a new drug has become more difficult to demonstrate and it has naturally slowed development. Now the reality remains that cardiovascular disease is still the leading cause of death in developed countries and rising quickly in the developing world, so I for one don’t think it’s prudent to abandon cardiovascular disease as a drug target although the challenges for industry are higher than they have ever been.
“Another problem is that we have a system which is seriously broken, in which the gate keepers, that is pharmacy benefit managers (PBMs), are financially incentivized to deny payments for drugs even when they have been shown to improve outcomes. There are perverse incentives for the PBMs in the way they are paid: the more often they deny access to medications, the more money they make. I have some ethical concerns about that.
“The other thing about the value equation that is broken is that you have a drug company like Mylan that can take a drug that costs pennies and raise the price to hundreds of dollars. Or take Valeant. At the Cleveland Clinic we spend 2 million a year in just one ICU on nitroprusside. If I had my druthers we could eliminate this price gouging so that the dollars that are available can be used to appropriately encourage innovation. If we spend all the healthcare dollars on Mylan’s bad behavior there’s less in the system to do good things, and that’s a problem for me.”